Perindopril 8 / indapamide 2.5 kрка
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INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT
Perindopril 2/indapamide 0.625 KRKA
Perindopril 4/indapamide 1.25 KRKA
Perindopril 8/indapamide 2.5 KRKA
(Perindopril 2/indapamide 0.625 KRKA
Perindopril 4/indapamide 1.25 KRKA
Perindopril 8/indapamide 2.5 KRKA)
Composition:
Active substances: perindopril tert-butylamine, indapamide;
One tablet contains 2 mg of perindopril tert-butylamine and 0.625 mg of indapamide, or 4 mg of perindopril tert-butylamine and 1.25 mg of indapamide, or 8 mg of perindopril tert-butylamine and 2.5 mg of indapamide;
Excipients: calcium chloride hexahydrate; lactose monohydrate; crospovidone; microcrystalline cellulose; sodium hydrocarbonate; colloidal anhydrous silicon dioxide; magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical characteristics:
Tablets 2 mg/0.625 mg: round, slightly biconvex tablets, white to almost white in color, with beveled edges and a short engraved line on one side;
Tablets 4 mg/1.25 mg: round, slightly biconvex tablets, white to almost white in color, with beveled edges and a score line on one side. The score line is intended to facilitate swallowing and is not intended for dividing the tablet into equal doses;
Tablets 8 mg/2.5 mg: round, slightly biconvex tablets, white to almost white in color, with a score line on one side. The score line is intended to facilitate swallowing and is not intended for dividing the tablet into equal doses.
Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme inhibitors. Perindopril and diuretics. ATC code C09BA04.
Pharmacological properties.
Pharmacodynamics.
Perindopril/indapamide is a combination of perindopril tert-butylamine salt, an angiotensin-converting enzyme (ACE) inhibitor, and indapamide, a sulfonamide diuretic. Its pharmacological effect is due to the properties of each component (perindopril and indapamide) and their additive synergy.
Mechanism of action
Related to perindopril/indapamide
Perindopril/indapamide is characterized by additional enhancement of the antihypertensive effect of both components.
Related to perindopril
Perindopril is an ACE inhibitor that converts angiotensin I into angiotensin II, a vasoconstrictive substance; in addition, the enzyme stimulates aldosterone secretion by the adrenal cortex and promotes degradation of the vasodilatory substance bradykinin into an inactive heptapeptide.
This leads to:
- reduction in aldosterone secretion;
- increased plasma renin activity, since aldosterone no longer induces a negative feedback response;
- decreased peripheral vascular resistance due to effects on muscular and renal vessels without salt and water retention or reflex tachycardia during continuous treatment.
Perindopril also exerts antihypertensive effects in patients with low and normal plasma renin levels.
Perindopril acts via its active metabolite – perindoprilat. Other metabolites are inactive.
Perindopril reduces cardiac load due to:
- vasodilatory effects on veins, possibly caused by changes in prostaglandin metabolism (reduced preload);
- reduction in total peripheral resistance (reduced afterload).
In studies conducted in patients with heart failure, the following were observed:
- reduced filling pressure in the left and right ventricles;
- reduced total peripheral vascular resistance;
- increased cardiac output and normalization of cardiac index;
- increased regional blood flow in muscles.
Significant improvement in exercise tolerance tests was observed.
Related to indapamide
Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide reduces sodium reabsorption in the cortical segment. It increases urinary excretion of sodium and chloride, and to a lesser extent, excretion of potassium and magnesium, thereby increasing diuresis and exerting antihypertensive effects.
Characteristics of antihypertensive effect
Related to perindopril/indapamide
In patients with arterial hypertension, regardless of age, the drug demonstrates a dose-dependent reduction in diastolic and systolic arterial pressure in both supine and standing positions.
This antihypertensive effect lasts for 24 hours. Normalization of arterial pressure is achieved in less than 1 month without tachyphylaxis; discontinuation of treatment does not lead to rebound increase in arterial pressure. In clinical trials, concomitant administration of perindopril and indapamide resulted in synergistic antihypertensive effects compared to administration of each component alone.
The effect of the low-dose combination perindopril/indapamide, 2 mg/0.625 mg, on cardiovascular morbidity and mortality has not been studied.
Related to perindopril
Perindopril is active in mild, moderate, and severe arterial hypertension. It reduces systolic and diastolic arterial pressure both in the supine and standing positions. Maximum hypotensive effect is achieved 4–6 hours after a single dose and lasts for at least 24 hours. A high level of residual ACE inhibition (approximately 80%) is maintained 24 hours after dosing.
In patients with reversible response, stabilization of arterial pressure occurs on average within 1 month of treatment and is maintained without tachyphylaxis.
Discontinuation of treatment is not associated with withdrawal syndrome.
Perindopril has vasodilatory properties and improves large artery elasticity, corrects structural changes in arteries, and reduces left ventricular hypertrophy. Additional therapy with a thiazide diuretic leads to additional synergism.
Combination of an ACE inhibitor with a thiazide reduces the risk of diuretic-induced hypokalemia compared to monotherapy with either component.
Related to indapamide
Indapamide as monotherapy exerts an antihypertensive effect lasting 24 hours. This occurs at doses where the diuretic effect is weak. Its antihypertensive action is associated with improved arterial elasticity and reduced arteriolar resistance and total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy.
Exceeding the recommended dose does not increase the therapeutic effect of thiazides or thiazide-like diuretics, while the number of adverse events increases. If treatment is insufficiently effective, dose escalation is not recommended.
Moreover, it has been demonstrated that in short-, medium-, and long-term treatment of patients with arterial hypertension, indapamide:
- has no effect on fat metabolism: triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol;
- has no effect on carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.
Clinical data on dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Concomitant use of ACE inhibitors and angiotensin receptor blockers was studied in two large-scale randomized controlled trials [ONTARGET (ONgoing Telmisartan Alone and Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)].
ONTARGET was a study involving patients with prior cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a study involving patients with type 2 diabetes and diabetic nephropathy.
The studies did not demonstrate significant beneficial effects on renal and/or cardiovascular morbidity and mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin receptor blockers.
Concomitant use of ACE inhibitors and angiotensin receptor blockers is contraindicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Endpoints) was a study assessing the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and/or chronic kidney disease and cardiovascular disease. The study was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular mortality, incidence of stroke, and reports of adverse events and serious complications (hyperkalemia, arterial hypotension, or impaired renal function) were more frequent in the aliskiren group compared to placebo.
Use in children
There are no data on the use of perindopril/indapamide in children.
Pharmacokinetics.
Related to perindopril/indapamide
Concomitant administration of perindopril and indapamide does not alter their pharmacokinetic properties compared to administration of the components separately.
Related to perindopril
Absorption and bioavailability
After oral administration, perindopril is rapidly absorbed in the gastrointestinal tract, with maximum plasma concentration reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour.
Since food intake reduces the conversion of perindopril to perindoprilat and thus decreases its bioavailability, perindopril tert-butylamine is recommended to be taken orally as a single daily dose in the morning before meals.
Distribution
The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Protein binding is low (less than 20% of perindoprilat binds to ACE), but depends on concentration.
Metabolism
Perindopril is a prodrug. 27% of the total absorbed perindopril is converted into the active metabolite perindoprilat. Additionally, five inactive metabolites are formed. Maximum plasma concentration of perindoprilat is reached within 3–4 hours.
Elimination
Perindoprilat is excreted in urine, and the half-life of the unbound fraction is approximately 17 hours, leading to steady-state conditions within 4 days.
Linearity/non-linearity
A linear relationship between perindopril dose and plasma concentration has been demonstrated.
Special populations
Elderly patients
In elderly individuals and patients with heart or renal failure, perindoprilat elimination is reduced.
Renal impairment
In renal impairment, dosage adjustment is recommended depending on the degree of impairment (creatinine clearance).
In case of dialysis
Perindoprilat is removed from circulation by dialysis, with a clearance rate of 70 mL/min.
Cirrhosis
In liver cirrhosis, perindopril kinetics are altered, with hepatic clearance of the parent molecule reduced by half; however, the amount of perindoprilat formed remains unchanged. Therefore, dose adjustment is not required in this condition (see sections "Special precautions" and "Dosage and administration").
Related to indapamide
Absorption
Indapamide is rapidly and almost completely absorbed in the gastrointestinal tract.
Distribution
Maximum plasma concentration of indapamide is reached approximately 1 hour after administration. Plasma protein binding of indapamide is 79%.
Biotransformation and elimination
The elimination half-life from plasma ranges from 14 to 24 hours (average 18 hours). Regular administration does not lead to accumulation of indapamide. 70% of indapamide is excreted primarily via the kidneys and 22% via feces as inactive metabolites.
Special populations
Renal impairment
Pharmacokinetic parameters of the drug remain unchanged in patients with renal impairment.
Clinical characteristics.
Indications.
Essential hypertension.
Contraindications.
Related to perindopril
- Hypersensitivity to perindopril or other ACE inhibitors.
- History of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors (see section "Special precautions").
- Hereditary or idiopathic angioedema.
- Concomitant use with medicinal products containing the active substance aliskiren in patients with diabetes mellitus or patients with renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").
- Pregnancy or women planning pregnancy.
- Concomitant use with sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").
- Extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").
- Significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section "Special precautions").
Related to indapamide
- Hypersensitivity to indapamide or to other sulfonamides.
- Severe renal impairment (creatinine clearance < 30 mL/min).
- Hepatic encephalopathy or severe hepatic dysfunction.
- Hypokalemia.
Related to the combination of perindopril/indapamide
- Hypersensitivity to any component of the medicinal product.
Due to lack of sufficient therapeutic experience, the combination of perindopril/indapamide should not be used:
- in patients undergoing dialysis;
- in patients with untreated decompensated heart failure.
Perindopril 2/indapamide 0.625 CRKA, Perindopril 4/indapamide 1.25 CRKA
- Severe renal function impairment (creatinine clearance < 30 mL/min).
Perindopril 8/indapamide 2.5 CRKA
- Severe and moderate renal function impairment (creatinine clearance < 60 mL/min).
Interaction with other medicinal products and other forms of interaction.
Common for perindopril and indapamide
Concomitant use not recommended
Lithium
Increases in serum lithium concentrations and signs of lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of perindopril with lithium is not recommended, but if combination therapy is necessary, careful monitoring of serum lithium levels is required.
Concomitant use requiring special monitoring
Baclofen: enhanced antihypertensive effect. Monitoring of blood pressure and renal function is required, and dosage adjustment may be necessary.
Non-steroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid at doses ≥3 g/day)
NSAIDs (including acetylsalicylic acid at anti-inflammatory doses, cyclooxygenase-2 inhibitors, and non-selective NSAIDs) may reduce the antihypertensive effect of ACE inhibitors. Additionally, NSAIDs and ACE inhibitors may additively increase serum potassium levels, potentially leading to renal dysfunction, including acute renal failure, especially in patients with pre-existing renal impairment. This combination should be used with caution, particularly in elderly patients. Adequate hydration should be ensured. Monitoring of renal function should be considered at initiation of concomitant therapy and periodically thereafter.
Concomitant use requiring attention
Tricyclic antidepressants (imipramine-like), neuroleptics: enhanced hypotensive effect and increased risk of orthostatic hypotension (additive effect).
Related to perindopril
Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Pharmacodynamics", "Contraindications", and "Special precautions").
Medicinal products causing hyperkalemia
Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with Perindopril/Indapamide CRKA. Some medicinal products or therapeutic classes may cause hyperkalemia, such as aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressive agents such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Combination with these agents increases the risk of hyperkalemia.
Therefore, concomitant use of Perindopril/Indapamide CRKA with the above-mentioned agents is not recommended. If concomitant use is necessary, it should be done with caution and frequent monitoring of serum potassium levels.
Contraindicated combinations (see section "Contraindications")
Aliskiren
Concomitant use of perindopril and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment due to increased risk of hyperkalemia, renal dysfunction, and cardiovascular morbidity and mortality (see section "Contraindications").
Extracorporeal treatments leading to blood contact with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g., polyacrylonitrile membranes) or low-density lipoprotein apheresis with dextran sulfate — increases the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.
Sacubitril/valsartan
Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as concomitant use of ACE inhibitors and sacubitril/valsartan increases the risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions").
Concomitant use not recommended
Aliskiren
Concomitant use of perindopril and aliskiren in all other patient groups, except those with diabetes mellitus or renal impairment, is not recommended due to increased risk of hyperkalemia, renal dysfunction, and cardiovascular morbidity and mortality (see section "Special precautions").
Concomitant therapy with ACE inhibitors and angiotensin receptor blockers
In patients with established atherosclerosis, heart failure, or diabetes mellitus with end-organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers has been associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and renal dysfunction (including acute renal failure) compared to monotherapy with RAAS-acting agents. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be considered only in selected cases with careful monitoring of renal function, serum potassium, and blood pressure.
Estramustine
Risk of increased incidence of adverse reactions such as angioedema.
Potassium-sparing diuretics (e.g., triamterene, amiloride…), potassium (salts)
Hyperkalemia (potentially fatal), especially when combined with renal dysfunction (additive hyperkalemic effect). Combination of perindopril with the above-mentioned agents is not recommended (see section "Special precautions"). However, if concomitant administration is necessary, it should be done with caution and careful monitoring of plasma potassium levels.
For use of spironolactone in heart failure, see section "Concomitant use requiring special monitoring".
Co-trimoxazole (trimethoprim/sulfamethoxazole)
Increased risk of hyperkalemia in patients concomitantly receiving co-trimoxazole (trimethoprim/sulfamethoxazole) (see section "Special precautions").
Concomitant use requiring special monitoring
Antidiabetic agents (insulin, oral hypoglycemic agents)
Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance glucose-lowering effects, increasing the risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment.
Diuretics not containing potassium
In patients taking diuretics, especially those with electrolyte imbalance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or increasing salt intake prior to starting perindopril therapy. Treatment should be initiated at low doses with gradual dose escalation.
In arterial hypertension, when a previously prescribed diuretic may have caused fluid/electrolyte depletion, it should be discontinued before starting ACE inhibitor therapy (diuretic use may be resumed later), or the ACE inhibitor should be started at a low dose with gradual dose increase.
In congestive heart failure on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose.
In any case, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.
Potassium-sparing diuretics (eplerenone or spironolactone)
Concomitant use of eplerenone or spironolactone at doses of 12.5–50 mg daily with low-dose ACE inhibitors is indicated:
- in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with ACE inhibitors and loop diuretics, there is a risk of potentially fatal hyperkalemia, especially if recommendations for combination use are not followed. Before initiating this combination, absence of hyperkalemia and renal impairment should be confirmed. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.
Racecadotril
ACE inhibitors (e.g., perindopril) are known to cause angioedema. This risk increases with concomitant use of racecadotril (a medicinal product used to treat acute diarrhea).
mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)
Increased risk of angioedema in patients concomitantly receiving mTOR inhibitors (see section "Special precautions").
Concomitant use requiring attention
Antihypertensive agents and vasodilators
Concomitant use of antihypertensive agents may enhance the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or other vasodilators may lead to additional blood pressure reduction.
Allopurinol, cytostatics or immunosuppressants, systemic corticosteroids (systemic use), or procainamide: concomitant use of these agents with ACE inhibitors may increase the risk of leukopenia (see section "Special precautions").
Anesthetics: ACE inhibitors may potentiate the hypotensive effects of certain anesthetics (see section "Special precautions").
Gold compounds: rare reactions similar to those seen with nitrates (facial flushing, nausea, vomiting, and arterial hypotension) may occur with concomitant use of ACE inhibitors, including perindopril, and injectable gold compounds (sodium aurothiomalate).
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)
Increased risk of angioedema when used concomitantly with an ACE inhibitor due to reduced dipeptidyl peptidase-IV (DPP-IV) activity by gliptins.
Sympathomimetics may attenuate the antihypertensive effect of ACE inhibitors.
Cyclosporine
Hyperkalemia may occur with concomitant use of ACE inhibitors and cyclosporine. Monitoring of serum potassium levels is recommended.
Heparin
Hyperkalemia may occur with concomitant use of ACE inhibitors and heparin. Monitoring of serum potassium levels is recommended.
Related to indapamide
Concomitant use requiring special attention
Medicinal products causing torsades de pointes ventricular tachycardia: indapamide should be used with caution when concomitantly administered with medicinal products causing torsades de pointes ventricular tachycardia, such as, but not limited to: class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide); class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide, bretylium); certain phenothiazine antipsychotics (e.g., chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol), other neuroleptics (pimozide); and other substances (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, intravenous vincamine, methadone, astemizole, terfenadine). Hypokalemia should be prevented and corrected if necessary; QT interval should be monitored.
Medicinal products lowering potassium levels, amphotericin B (intravenous), systemic glucocorticoids and mineralocorticoids (systemic administration), tetracosactide, stimulant laxatives: increased risk of hypokalemia (additive effect). Serum potassium levels should be checked and corrected if necessary; particular caution is required when using cardiac glycosides. Stimulant laxatives should not be used.
Cardiac glycosides: hypokalemia and/or hyponatremia may potentiate the toxic effects of cardiac glycosides. Monitoring of plasma potassium and magnesium levels and ECG is recommended, and therapy should be reviewed if necessary.
Allopurinol
Concomitant use with indapamide may increase the frequency of hypersensitivity reactions to allopurinol.
Concomitant use requiring monitoring
Potassium-sparing diuretics (amiloride, spironolactone, triamterene)
Despite the rationale for using this combination in some patients, hypokalemia or hyperkalemia may occur (especially in patients with renal impairment or diabetes mellitus). Plasma potassium levels should be monitored, ECG monitoring should be performed, and therapy should be reviewed if necessary.
Metformin: in functional renal impairment related to diuretic use, particularly loop diuretics, the risk of lactic acidosis with metformin use increases. Metformin should not be used if plasma creatinine levels exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.
Iodinated contrast agents: in case of dehydration related to diuretic use, the risk of acute renal failure increases with iodinated contrast agents, especially at high doses. Fluid balance should be restored before administration of iodinated contrast agents.
Calcium salts: risk of hypercalcemia due to reduced renal excretion of calcium.
Cyclosporine, tacrolimus: risk of increased plasma creatinine concentration without changes in cyclosporine blood levels, even without fluid/salt volume reduction.
Corticosteroids, tetracosactide (systemic administration)
Reduced antihypertensive effect (salt and water retention due to corticosteroids).
Special precautions.
Warnings common to perindopril and indapamide
Lithium
Concomitant use of lithium and perindopril/indapamide combinations is generally not recommended.
Related to perindopril
Dual blockade of the RAAS
Concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren has been associated with increased incidence of arterial hypotension, loss of consciousness, hyperkalemia, and renal dysfunction (including acute renal failure). Dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is therefore not recommended. However, it may be used in individual cases if necessary, under strict monitoring of renal function, potassium levels, and blood pressure.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Neutropenia/agranulocytosis/thrombocytopenia/anemia
Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been observed in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors during ACE inhibitor therapy. Perindopril should be used with particular caution in treating patients with collagen vascular diseases or those receiving immunosuppressants, allopurinol, or procainamide, as well as in combination with some of these risk factors, especially in the presence of impaired renal function. Severe infections have developed in some patients, which in certain cases were unresponsive to intensive antibiotic therapy. If perindopril is used to treat such patients, periodic monitoring of white blood cell counts should be performed, and patients should be instructed to report any signs of infection (e.g., sore throat, fever) (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").
Renovascular hypertension
In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal failure (see section "Contraindications"). Diuretic therapy may be a contributing factor. Decreased renal function may be associated with only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.
Hypersensitivity/angioedema
In patients treated with ACE inhibitors, including perindopril, angioedema of the face, lips, mucous membranes, tongue, pharynx, and/or larynx has occurred in some cases. It may occur at any time during treatment. In such cases, perindopril must be discontinued immediately and careful monitoring should be initiated until symptoms completely resolve. In cases of facial and lip swelling, the condition may improve without treatment, but antihistamines may alleviate symptoms.
Laryngeal angioedema can be fatal. Swelling of the tongue, glottis, or larynx may lead to airway obstruction. In these cases, emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 solution (0.3–0.5 mL) and/or maintaining airway patency.
ACE inhibitors cause angioedema more frequently in patients of African descent than in patients of other races.
Patients with a history of angioedema unrelated to ACE inhibitor use have an increased risk of developing angioedema when taking ACE inhibitors.
Intestinal angioedema has been rarely reported in patients taking ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema, and C-1 esterase levels were normal. Intestinal angioedema was diagnosed by procedures including abdominal computed tomography or ultrasound, or during surgical intervention, and symptoms improved after discontinuation of the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients taking ACE inhibitors who present with abdominal pain.
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications"). Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If sacubitril/valsartan is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Concomitant use of ACE inhibitors with neutral endopeptidase inhibitors (NEP) (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (including swelling of the airways or tongue, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already taking ACE inhibitors.
Anaphylactoid reactions during desensitization
In patients taking ACE inhibitors during desensitization procedures (e.g., to wasp or bee venom), isolated cases of prolonged, life-threatening anaphylactoid reactions have been reported. ACE inhibitors should be used with caution in patients with allergies undergoing desensitization procedures and should be avoided in those undergoing immunotherapy with venom. However, these reactions can be prevented by temporarily discontinuing ACE inhibitors at least 24 hours before treatment in patients who require both ACE inhibitors and desensitization.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
Rarely, life-threatening anaphylactoid reactions have occurred in patients taking ACE inhibitors during LDL apheresis with dextran sulfate. These reactions can be prevented by temporarily discontinuing ACE inhibitors before each apheresis session.
Patients undergoing hemodialysis
Anaphylactoid reactions have been observed in patients undergoing dialysis with high-flux membranes (e.g., AN 69®) who are also taking ACE inhibitors. For such patients, consideration should be given to using alternative types of dialysis membranes or another class of antihypertensive agents.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting via inhibition of the RAAS. Therefore, this medicinal product is not recommended for such patients.
Potassium-sparing agents, potassium supplements, or potassium-containing salt substitutes
Combining potassium-sparing agents, potassium supplements, or potassium-containing salt substitutes with perindopril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Pregnancy
ACE inhibitor therapy should not be initiated during pregnancy. If continuation of antihypertensive therapy is considered essential, women planning pregnancy should be switched to alternative antihypertensive agents with proven safety data during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately, and if necessary, alternative therapy with a medicinal product approved for use in pregnant women should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Related to indapamide
Hepatic encephalopathy
In patients with impaired liver function, the use of thiazide and thiazide-like diuretics may precipitate encephalopathy, particularly in the presence of electrolyte imbalances, which may progress to hepatic coma. In such cases, diuretic therapy should be discontinued immediately.
Photosensitivity
Cases of photosensitivity reactions have been reported in patients taking thiazide and thiazide-like diuretics. If such reactions occur, diuretic therapy should be discontinued. If diuretics must be restarted, vulnerable areas should be protected from sunlight or artificial ultraviolet sources.
Common to perindopril and indapamide
Renal function impairment
Treatment with the perindopril/indapamide combination is contraindicated in severe renal impairment (creatinine clearance < 30 mL/min). Treatment with Perindopril 8/indapamide 2.5 CRKA is contraindicated in moderate to severe renal impairment (creatinine clearance < 60 mL/min).
If laboratory signs of renal impairment develop in patients with arterial hypertension without pre-existing visible signs of renal dysfunction during treatment, the drug should be discontinued, with possible resumption of therapy at a lower dose or with one of the components. Such patients require monitoring of potassium and creatinine levels two weeks after initiation of treatment and every two months during therapeutic stabilization. Cases of renal impairment have been observed predominantly in patients with severe heart failure or pre-existing renal dysfunction, including those with renal artery stenosis.
The drug is not recommended for patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.
Arterial hypotension and water and electrolyte deficiency
There is a risk of sudden blood pressure reduction in patients with existing sodium deficiency (especially in patients with renal artery stenosis). Therefore, it is necessary to systematically check for signs of water and electrolyte deficiency, which may occur due to vomiting or diarrhea.
Such patients require regular monitoring of plasma electrolyte levels.
In cases of significant arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required. Transient arterial hypotension is not a contraindication for further drug use. After restoration of circulating blood volume and normalization of blood pressure, treatment may be resumed at a lower dose or with one of the components.
Potassium levels
The combination of perindopril and indapamide does not exclude the possibility of hypokalemia, especially in patients with diabetes mellitus or renal insufficiency. As with any other diuretic-containing drug, regular monitoring of potassium levels should be performed.
Excipients
Due to the presence of lactose in the formulation, this medicinal product should not be administered to patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Related to perindopril
Cough
A dry, non-productive, persistent cough may occur during ACE inhibitor therapy, which resolves after discontinuation of treatment. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. If ACE inhibitor therapy remains the preferred option, continuation of treatment may be considered.
Risk of arterial hypotension and/or renal failure (in heart failure, water and electrolyte imbalance)
Significant stimulation of the RAAS, particularly during significant water and electrolyte imbalance (strict low-sodium diet or prolonged diuretic therapy), has been observed in patients with initially low blood pressure, renal artery stenosis, heart failure with congestion, or cirrhosis with edema and ascites.
Thus, blockade of this system by an ACE inhibitor may cause, especially at the start of treatment and during the first 2 weeks, unexpected sudden reduction in blood pressure and/or increase in plasma creatinine levels, indicating functional renal failure. This may occasionally occur as an acute episode, although rarely, with varying onset periods.
In such cases, treatment should be initiated with a low dose, and the dose should be gradually increased.
Elderly patients
Renal function and potassium levels should be checked before starting treatment. The initial dose should be adjusted according to blood pressure response, especially in the presence of water and electrolyte imbalance, to avoid unexpected arterial hypotension.
Atherosclerosis
The risk of arterial hypotension exists in all patients, but particular attention should be paid to patients with ischemic heart disease or impaired cerebral circulation. Such patients should start treatment with a low dose.
Renovascular hypertension
The treatment of renovascular hypertension is revascularization. However, ACE inhibitors may be acceptable for patients with renovascular hypertension awaiting surgical correction or when such surgery is not possible.
The use of Perindopril 8/indapamide 2.5 CRKA is not recommended in patients with known or suspected renal artery stenosis, as treatment should be initiated in hospital with a dose lower than Perindopril 8/indapamide 2.5 CRKA.
The use of ACE inhibitors in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney increases the risk of hypotension and renal failure (see section "Contraindications"). Diuretic therapy may be a contributing factor. Loss of renal function may manifest only as minor changes in plasma creatinine levels, even in patients with stenosis of one renal artery.
If the perindopril/indapamide combination is prescribed to patients with known or suspected renal artery stenosis, treatment should be initiated in hospital with a low dose, and renal function and potassium levels should be monitored, as functional renal failure, reversible upon discontinuation of treatment, has occurred in some patients.
Heart failure/severe heart failure
In patients with severe heart failure (NYHA class IV), treatment should be initiated under medical supervision with a reduced initial dose; therefore, Perindopril 8/indapamide 2.5 CRKA is not suitable for initiating treatment. Beta-blockers should not be discontinued in hypersensitive patients with coronary insufficiency: an ACE inhibitor should be added to the beta-blocker.
Patients with diabetes mellitus
In patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to increased potassium levels), treatment with Perindopril 8/indapamide 2.5 CRKA is not advisable, as treatment should be initiated under medical supervision with a reduced initial dose.
Patients with diabetes mellitus taking oral antidiabetic agents or insulin require careful monitoring of blood glucose levels during the first months of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").
Racial origin
As with other ACE inhibitors, perindopril may be less effective in reducing blood pressure in patients of African descent compared to patients of other races, possibly due to the higher prevalence of low-renin states in patients of African descent.
Surgery/general anesthesia
ACE inhibitors may cause arterial hypotension during anesthesia, especially when the anesthetic agent has hypotensive potential.
Therefore, it is recommended that treatment with long-acting ACE inhibitors, such as perindopril, be discontinued, if possible, one day before surgical intervention.
Aortic and mitral valve stenosis/hypertrophic cardiomyopathy
ACE inhibitors should be used with caution in treating patients with left ventricular outflow tract obstruction.
Hepatic insufficiency
Treatment with ACE inhibitors has occasionally been associated with a syndrome beginning as cholestatic jaundice progressing to fulminant hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome is not established. If jaundice or significant elevation of liver enzyme activity occurs, ACE inhibitor therapy should be discontinued, and medical monitoring and treatment should be initiated.
Hyperkalemia
Increased serum potassium concentration has been observed in some patients taking ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal impairment or reduced renal function, age (over 70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other medicinal products that increase serum potassium concentration (such as heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole, aldosterone antagonists or angiotensin receptor blockers, acetylsalicylic acid ≥ 3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If such concomitant therapy is necessary, serum potassium levels should be monitored regularly.
Related to indapamide
Water and electrolyte balance
Plasma sodium levels
Plasma sodium concentration should be determined before starting treatment and at regular intervals during treatment. Since a decrease in plasma sodium concentration may initially be asymptomatic, regular monitoring is essential. Plasma sodium concentration should be measured more frequently in elderly patients and those with liver cirrhosis (see sections "Overdose" and "Side effects").
Any diuretic therapy may cause hyponatremia, sometimes with very serious consequences. Hyponatremia with hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis: the frequency and extent of this effect are minor.
Plasma potassium levels
The main risk of thiazide and thiazide-like diuretic therapy is sudden reduction in potassium concentration and hypokalemia. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis have been reported, mainly in association with severe hypoglycemia. Hypokalemia should be prevented in poorly nourished patients and/or those taking multiple medications, elderly patients, patients with liver cirrhosis and ascites, ischemic heart disease, and heart failure (< 3.4 mmol/L).
In such patients, hypokalemia increases the cardiotoxicity of digitalis drugs and the risk of arrhythmias.
Patients with prolonged QT interval are also at risk, whether the cause is hereditary or iatrogenic. Hypokalemia (and bradycardia) are thus factors predisposing to dangerous arrhythmias, including polymorphic ventricular tachycardia of the torsades de pointes type, sometimes with fatal outcome.
In all such cases, plasma potassium levels should be monitored more frequently. The first measurement of plasma potassium concentration should be performed within the first week after starting treatment.
If low potassium levels are detected, dose adjustment should be performed. Hypokalemia associated with low serum magnesium concentration may be resistant to treatment unless serum magnesium levels are corrected.
Magnesium levels
Thiazide and thiazide-like diuretics, including indapamide, have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").
Calcium levels
Thiazide and thiazide-like diuretics may reduce calcium excretion in urine and cause a slight transient increase in plasma calcium concentration. Persistent hypercalcemia may indicate hyperparathyroidism. Therefore, diuretic therapy should be discontinued until parathyroid function is evaluated.
Blood glucose
In patients with diabetes mellitus, blood glucose levels should be monitored carefully, particularly in the presence of hypokalemia.
Uric acid
In patients with hyperuricemia, there may be a tendency to gout attacks.
Renal function and diuretics
Thiazide and related diuretics are more effective with normal renal function or mild impairment (plasma creatinine level in adults < 25 mg/L or 220 µmol/L).
In elderly patients, plasma creatinine levels should be adjusted according to age, body weight, and sex using the Cockcroft formula:
clcr = (140 - age) × body weight / 0.814 × plasma creatinine level,
where: age is in years, body weight is in kilograms, plasma creatinine level is in µmol/L.
The formula is suitable for elderly men and should be adapted for women by multiplying the result by 0.85.
Hypovolemia arising at the beginning of treatment due to loss of water and sodium caused by diuretic use may lead to reduced glomerular filtration. This may result in increased plasma urea and creatinine levels. In patients with normal renal function, this transient functional renal failure resolves without consequences, but in patients with pre-existing renal impairment, it may worsen the condition.
Athletes
Athletes should be aware that this drug contains an active substance (indapamide) that may lead to a positive doping test.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Untreated acute angle-closure glaucoma may lead to permanent vision loss. Symptoms have an acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug. Primary treatment is discontinuation of the drug as soon as possible. If intraocular pressure remains uncontrolled, prompt medical or surgical treatment may be required. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.
Use during pregnancy or breastfeeding.
Pregnancy
The drug is contraindicated in pregnant women or women planning pregnancy.
Warnings related to perindopril
ACE inhibitor therapy should not be initiated during pregnancy. In cases where continuation of ACE inhibitor therapy is considered essential, women planning pregnancy should be switched to alternative antihypertensive agents with proven safety data during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use in pregnant women.
It is known that ACE inhibitor use during the second and third trimesters of pregnancy causes toxic effects on the embryo (renal dysfunction, oligohydramnios, delayed formation of cranial bone tissue) and on the newborn (renal failure, arterial hypotension, hyperkalemia).
If ACE inhibitors were used during the second and third trimesters, ultrasound examination of renal function and cranial structure of the newborn is recommended.
Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored for timely detection and correction of arterial hypotension.
Warnings related to indapamide
Data on indapamide use during pregnancy are limited (fewer than 300 pregnancy cases). Prolonged use of a thiazide diuretic during the third trimester may reduce circulating blood volume in the pregnant woman and uteroplacental perfusion, potentially causing fetoplacental ischemia and delayed fetal development. Animal studies do not indicate direct or indirect harmful effects on reproductive toxicity.
As a precautionary measure, indapamide use during pregnancy should be avoided.
Breastfeeding period
The drug is not recommended for use during breastfeeding. A decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the therapy for the mother.
Warnings related to perindopril
Perindopril use during breastfeeding is not recommended due to lack of data in this patient group. Alternative therapy with a proven safety profile should be preferred, especially during breastfeeding of a newborn or premature infant.
Warnings related to indapamide
There is insufficient information on the passage of indapamide/metabolites into human milk. Increased sensitivity to sulfonamide-derived drugs and hypokalemia may occur. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide diuretics, which during breastfeeding suppress milk secretion.
Indapamide is not recommended for use during breastfeeding.
Fertility
Reproductive toxicity studies did not show effects on fertility in male and female rats. There is no effect on human fertility.
Ability to affect reaction speed when driving vehicles or operating machinery.
Neither of the two active substances nor their combination directly affects attention, but individual reactions related to low blood pressure may occur in some patients, especially at the beginning of treatment or in combination with other antihypertensive drugs.
As a result, the ability to drive vehicles or operate machinery may be impaired.
Method of Administration and Dosage
For oral use.
Perindopril 2/Indapamide 0.625 KRKA
The usual dose is 1 tablet of Perindopril 2/Indapamide 0.625 KRKA once daily, preferably taken in the morning before a meal. If blood pressure is not adequately controlled after one month of treatment, the dose may be doubled.
Perindopril 4/Indapamide 1.25 KRKA
One tablet of Perindopril 4/Indapamide 1.25 KRKA should be taken once daily, preferably in the morning before a meal.
Whenever possible, individual dose titration with the separate components is recommended.
Perindopril 8/Indapamide 2.5 KRKA
One tablet of Perindopril 8/Indapamide 2.5 KRKA should be taken once daily, preferably in the morning before a meal.
The maximum daily dose is 1 tablet of Perindopril 8/Indapamide 2.5 KRKA.
Special Patient Groups
Elderly Patients
Perindopril 2/Indapamide 0.625 KRKA
Treatment should be initiated with the usual dose – 1 tablet of Perindopril 2/Indapamide 0.625 KRKA daily.
Perindopril 4/Indapamide 1.25 KRKA
Treatment should be initiated according to the response of arterial pressure and renal function.
Perindopril 8/Indapamide 2.5 KRKA
In elderly patients, plasma creatinine levels should be adjusted according to age, body weight, and gender. Treatment may be prescribed in elderly patients if renal function is normal and according to the response of arterial pressure.
Renal Impairment
Perindopril 2/Indapamide 0.625 KRKA, Perindopril 4/Indapamide 1.25 KRKA
Treatment is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), treatment should be initiated using appropriate doses of the individual components of the drug. Patients with creatinine clearance ≥ 60 mL/min do not require dose adjustment. Routine medical monitoring should include careful assessment of plasma creatinine and potassium levels.
Perindopril 8/Indapamide 2.5 KRKA
Treatment is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Patients with moderate renal impairment do not require dose adjustment.
Hepatic Impairment
Treatment is contraindicated in patients with severe hepatic impairment.
Dose adjustment is not required in patients with moderate hepatic impairment.
Children
The drug is not recommended for use in children due to insufficient data on safety and efficacy in this patient group.
Overdose
Possible symptoms include: arterial hypotension, nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria progressing to anuria (due to hypovolemia). Electrolyte and fluid imbalances (low sodium levels, low potassium levels) may also occur.
Treatment: Immediate management includes rapid removal of the drug from the body by gastric lavage and/or administration of activated charcoal, followed by restoration of fluid and electrolyte balance in a medical facility. If arterial hypotension occurs, the patient should be placed in a supine position with the legs slightly lowered. Recommended treatment includes intravenous administration of 0.9% sodium chloride solution or any other method of volume expansion. Perindopril can be removed from systemic circulation by hemodialysis (see section "Pharmacokinetics"). Continuous monitoring of vital signs, serum electrolytes, and creatinine levels is required.
Side effects
Summary of safety profile
Administration of perindopril suppresses the RAAS and tends to reduce potassium losses caused by indapamide.
Hypokalemia (potassium level <3.4 mmol/L) was observed in:
- 2% of patients treated with perindopril/indapamide 2 mg/0.625 mg tablets;
- 4% of patients treated with perindopril/indapamide 4 mg/1.25 mg tablets;
- 6% of patients treated with perindopril/indapamide 8 mg/2.5 mg tablets.
Most commonly observed side effects:
- With perindopril: dizziness, headache, paraesthesia, taste disturbances, visual disturbances, vertigo, tinnitus, hypotension, cough, dyspnea, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia;
- With indapamide: hypokalemia, hypersensitivity reactions (mainly dermatological), particularly in patients predisposed to allergic and asthmatic reactions, and maculopapular eruptions.
List of side effects
Adverse reactions that may occur during treatment are classified according to the following frequency:
Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).
| System Organ Class |
Adverse Reactions |
Frequency |
||
| Perindopril |
Indapamide |
|||
| Infections and infestations |
Rhinitis |
Very rare |
- |
|
| Blood and lymphatic system disorders |
Eosinophilia |
Uncommon1) |
- |
|
| Agranulocytosis2) |
Very rare |
Very rare |
||
| Aplastic anemia |
- |
Very rare |
||
| Pancytopenia |
Very rare |
- |
||
| Leukopenia |
Very rare |
Very rare |
||
| Neutropenia2) |
Very rare |
- |
||
| Hemolytic anemia |
Very rare |
Very rare |
||
| Thrombocytopenia2) |
Very rare |
Very rare |
||
| Immune system disorders |
Hypersensitivity reactions (mainly dermatological, in patients predisposed to allergic and asthmatic reactions and maculopapular rashes) |
- |
Common |
|
| Endocrine system disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
Uncommon |
- |
|
| Metabolism and nutrition disorders |
Hypoglycemia3) |
Uncommon1) |
- |
|
| Hyperkalemia, reversible upon discontinuation2) |
Uncommon1) |
- |
||
| Hypnatremia2) |
Uncommon1) |
Uncommon |
||
| Hypercalcemia |
- |
Very rare |
||
| Hypokalemia2) |
- |
Common |
||
| Hypochloremia |
- |
Uncommon |
||
| Hypomagnesemia |
- |
Uncommon |
||
| Psychiatric disorders |
Mood disorders |
Uncommon |
||
| Sleep disorders |
Uncommon |
|||
| Depression |
Uncommon |
- |
||
| Confusion |
Very rare |
- |
||
| Nervous system disorders |
Dizziness |
Common |
- |
|
| Headache |
Common |
Uncommon |
||
| Paresthesia |
Common |
Uncommon |
||
| Taste disturbance |
Common |
- |
||
| Somnolence |
Uncommon1) |
- |
||
| Syncope |
Uncommon1) |
Unknown |
||
| Stroke, possibly secondary to excessive hypotension in patients at high risk2) |
Very rare |
- |
||
| Development of hepatic encephalopathy in liver insufficiency2) |
- |
Unknown |
||
| Eye disorders |
Visual disturbance |
Common |
Unknown |
|
| Myopia2) |
- |
Unknown |
||
| Blurred vision |
- |
Unknown |
||
| Acute angle-closure glaucoma |
- |
Unknown |
||
| Choroidal effusion |
- |
Unknown |
||
| Ear and labyrinth disorders |
Vertigo |
Common |
Uncommon |
|
| Tinnitus |
Common |
- |
||
| Cardiac disorders |
Pounding heartbeat |
Uncommon1) |
- |
|
| Tachycardia |
Uncommon1) |
- |
||
| Angina pectoris2) |
Very rare |
- |
||
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
Very rare |
Very rare |
||
| Myocardial infarction, possibly secondary to excessive hypotension in patients at high risk2) |
Very rare |
- |
||
| Paroxysmal ventricular tachycardia of the "torsades de pointes" type (potentially fatal) 3) |
Unknown |
|||
| Vascular disorders |
Arterial hypotension (and symptoms related to hypotension)2) |
Common |
Very rare |
|
| Vasculitis |
Uncommon1) |
- |
||
| Flushing |
Uncommon |
- |
||
| Raynaud's phenomenon |
Unknown |
- |
||
| Respiratory, thoracic and mediastinal disorders |
Cough2) |
Common |
- |
|
| Dyspnea |
Common |
- |
||
| Bronchospasm |
Uncommon |
- |
||
| Eosinophilic pneumonia |
Very rare |
- |
||
| Gastrointestinal disorders |
Abdominal pain |
Common |
- |
|
| Constipation |
Common |
Uncommon |
||
| Diarrhea |
Common |
- |
||
| Dyspepsia |
Common |
- |
||
| Nausea |
Common |
Uncommon |
||
| Vomiting |
Common |
Uncommon |
||
| Dry mouth |
Uncommon |
Uncommon |
||
| Pancreatitis |
Very rare |
Very rare |
||
| Hepatobiliary disorders |
Hepatitis2) |
Very rare |
Unknown |
|
| Liver function abnormalities |
- |
Very rare |
||
| Skin and subcutaneous tissue disorders |
Pruritus |
Common |
- |
|
| Rash |
Common |
- |
||
| Maculopapular rash |
- |
Common |
||
| Urticaria2) |
Uncommon |
Very rare |
||
| Angioedema2) |
Uncommon |
Very rare |
||
| Purpura |
- |
Uncommon |
||
| Hyperhidrosis |
Uncommon1) |
- |
||
| Photosensitivity reaction |
Uncommon1) |
Unknown |
||
| Pemphigoid |
Uncommon |
- |
||
| Worsening of psoriasis symptoms |
Uncommon1) |
- |
||
| Multiform erythema |
Very rare |
- |
||
| Toxic epidermal necrolysis |
- |
Very rare |
||
| Stevens-Johnson syndrome |
- |
Very rare |
||
| Musculoskeletal and connective tissue disorders |
Muscle cramps |
Common |
Unknown |
|
| Exacerbation of pre-existing systemic lupus erythematosus |
- |
Unknown |
||
| Arthralgia |
Uncommon1) |
- |
||
| Myalgia |
Uncommon1) |
- |
||
| Muscle weakness |
- |
Unknown |
||
| Rhabdomyolysis |
- |
Unknown |
||
| Renal and urinary disorders |
Renal impairment |
Uncommon |
- |
|
| Acute renal failure |
Uncommon |
Very rare |
||
| Anuria/oliguria |
Uncommon |
- |
||
| Reproductive system and breast disorders |
Erectile dysfunction |
Uncommon |
Uncommon |
|
| General disorders and administration site conditions |
Asthenia |
Common |
- |
|
| Chest pain |
Uncommon1) |
- |
||
| Malaise |
Uncommon1) |
- |
||
| Peripheral edema |
Uncommon1) |
- |
||
| Pyrexia |
Uncommon1) |
- |
||
| Fatigue |
- |
Uncommon |
||
| Investigations |
Increased plasma urea levels |
Uncommon1) |
- |
|
| Increased plasma creatinine levels |
Uncommon1) |
- |
||
| Increased plasma bilirubin levels |
Uncommon |
- |
||
| Elevated liver enzymes |
Uncommon |
Unknown |
||
| Decreased hemoglobin and red blood cell volume in blood2) |
Very rare |
- |
||
| Increased plasma glucose levels |
- |
Unknown |
||
| Increased plasma uric acid levels |
- |
Unknown |
||
| QT interval prolongation on ECG3) |
- |
Unknown |
||
| Injury, poisoning and procedural complications |
Falls |
Uncommon1) |
- |
|
- The frequency of adverse reactions is based on spontaneous reports during clinical trials.
- See section "Special precautions for use".
- See sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".
Description of selected adverse reactions
During phase II and III comparative studies of 1.5 mg and 2.5 mg indapamide, plasma potassium analysis revealed a dose-dependent effect of indapamide:
Indapamide 1.5 mg: plasma potassium level < 3.4 mmol/L was observed in 10% of patients and < 3.2 mmol/L in 4% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the average decrease in plasma potassium level was 0.23 mmol/L.
Indapamide 2.5 mg: plasma potassium level < 3.4 mmol/L was observed in 25% of patients and < 3.2 mmol/L in 10% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the average decrease in plasma potassium level was 0.41 mmol/L.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.
Shelf life. 3 years.
Storage conditions.
Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture.
Keep out of reach and sight of children.
Packaging.
10 tablets in a blister; 3 or 9 blisters in a cardboard box.
15 tablets in a blister; 2 or 6 blisters in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and place of business.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.